T-cell receptor (TCR) diversity of virusspecific CD8 ؉ T cells likely helps prevent escape mutations in chronic viral infections. To understand the dynamics of the virus-specific T cells in more detail, we followed the evolution of the TCR repertoire specific for a dominant HLA-B*08-restricted epitope in Nef (FLKEKGGL) in a cohort of subjects infected with HIV. Epitope-specific CD8 ؉ T cells used structurally diverse TCR repertoires, with different TCR␤ variable regions and with high amino acid diversity within antigen recognition sites. In a longitudinal study, distinct V␤ populations within the HIVspecific TCR repertoire expanded simultaneously with changes in plasma viremia, whereas other V␤ populations remained stable or even decreased. Despite antigenic variation in some subjects, all subjects had the consensus sequence present during the study period. Functional analysis of distinct V␤ populations revealed differences in HIV-specific IFN-␥ secretion ex vivo as well as differences in tetramer binding, indicating functional heterogeneity among these populations. This contrasts with findings in a subject on antiretroviral therapy with suppression of viremia to less than 50 copies/mL, where we observed long-term persistence of a single clonotype. Our findings illustrate the flexibility of a heterogeneous HIV-1-specific CD8 ؉ TCR repertoire in subjects with partial control of viremia. (Blood. 2006;107:2373-2383)

Risk factors associated with respiratory failure during respiratory syncytial virus (RSV) infection have not been assessed in adults. We identified RSV by quantitative reverse transcription polymerase chain reaction in 58 adults during the 2007–2008 winter. Clinical variables and respiratory secretion viral loads were compared in 26 outpatients and 32 inpatients. Cardiopulmonary diseases were more common among inpatients than outpatients (91% vs 31%, P = .0001), whereas mean RSV load was similar. Nasal viral load was higher in ventilated vs nonventilated hospitalized patients (log10 3.7 ± 1.7 plaque-forming units (PFUs)/mL vs 2.4 ± 1.1 PFUs/mL, P = .02), and high viral load was independently associated with respiratory failure.

After initiation of antiretroviral therapy (ART), HIV loads and frequencies of HIV epitope-specific immune responses decrease.A diverse virus-specific T cell receptor (TCR) repertoire allows the host to respond to viral epitope diversity, but the effect of antigen reduction as a result of ART on the TCR repertoire of epitope-specific CD8 ؉ T cell populations has not been well defined. We determined the TCR repertoires of 14 HIV-specific CD8 ؉ T cell responses from 8 HIV-positive individuals before and after initiation of ART. We used multiparameter flow cytometry to measure the distribution of memory T cell subsets and the surface expression of PD-1 on T cell populations and T cell clonotypes within epitope-specific responses from these individuals. Post-ART, we noted decreases in the frequency of circulating epitope-specific T cells (P ‫؍‬ 0.02), decreases in the number of T-cell clonotypes found within epitope-specific T cell receptor repertoires (P ‫؍‬ 0.024), and an overall reduction in the amino acid diversity within these responses (P < 0.0001). Despite this narrowing of the T cell response to HIV, the overall hierarchy of dominant T cell receptor clonotypes remained stable compared to that pre-ART. CD8؉ T cells underwent redistributions in memory phenotypes and a reduction in CD38 and PD-1 expression post-ART. Despite extensive remodeling at the structural and phenotypic levels, PD-1 was expressed at higher levels on dominant clonotypes within epitope-specific responses before and after initiation of ART. These data suggest that the antigen burden may maintain TCR diversity and that dominant clonotypes are sensitive to antigen even after dramatic reductions after initiation of ART.

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